Decoding reno-protective mechanisms in mouse Pkhd1 models: Implications for ARPKD therapeutics

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PROJECT SUMMARY There are ~1,500 patients in the United States with autosomal recessive polycystic kidney disease (ARPKD; MIM 173900), a hepatorenal fibrocystic disorder characterized by enlarged kidneys with innumerable collecting duct cysts and progressive loss of renal function. Essentially all cases of ARPKD can be attributed to mutations in PKHD1, which encodes a single-pass transmembrane protein, fibrocystin/polyductin (FPC). We currently have very little insight into the pathogenesis of human ARPKD and thus, treatment is largely supportive. Striking species-specific differences in the PKHD1/Pkhd1 renal phenotype may offer important insights into disease mechanisms. While human patients with either missense or truncating PKHD1 mutations have severe renal cystic disease, mouse Pkhd1 models with engineered truncating mutations (and presumably loss of FPC function) express minimal or no renal disease. Our preliminary studies reveal that while MYC is overexpressed in human ARPKD kidneys, Myc is not overexpressed in mouse Pkhd1 kidneys. In previous studies, we have shown that FPC undergoes Notch-like processing with cleavage of the carboxy terminus (FPC-CTD) from the plasma membrane and nuclear trafficking. Here, we demonstrate that the mouse FPC-CTD binds directly to the Myc P1 promoter and increases Myc expression. Based on these findings, we hypothesize that mouse renal epithelia can compensate for the loss of FPC-CTD function through reno-protective mechanisms and that species-specific, FPC-CTD regulation of Myc expression is central to this reno-protection. We speculate that while these mechanisms are not normally operative in human renal epithelia, they may identify new opportunities for therapeutic targeting in human ARPKD renal disease. We propose two specific aims to test our hypothesis: (1) define how the FPC-CTD regulates Myc/MYC expression in mouse and human renal epithelia and determine whether disruption of the proposed regulatory circuits is a central driver of renal cystogenesis; and (2) compare the FPC-CTD nuclear interactome in mouse and human renal epithelia and test whether differences in transcriptional targets identifies reno-protective pathways in mouse kidneys. Our studies will advance the field by sequentially addressing the transcriptional role of FPC-CTD. Specifically, we will: 1) determine mouse Pkhd1 models; how FPC-CTD related Myc transcriptional regulation contributes to reno-protection in and 2) identify putative mechanisms that allow mouse renal epithelia to compensate for the loss of FPC-CTD nuclear function. Moving forward, these data will lay the foundation for translating mouse reno-protective mechanisms into novel, therapeutic strategies that attenuate human PKHD1-related renal cystic disease.